CN114340639A - Boronic acid derivatives and their therapeutic use - Google Patents

Boronic acid derivatives and their therapeutic use Download PDF

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CN114340639A
CN114340639A CN202080059598.5A CN202080059598A CN114340639A CN 114340639 A CN114340639 A CN 114340639A CN 202080059598 A CN202080059598 A CN 202080059598A CN 114340639 A CN114340639 A CN 114340639A
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compound
bacteroides
yersinia
pharmaceutically acceptable
bordetella
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奥尔加·洛莫夫思卡亚
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Qpex Biopharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compound compositions, pharmaceutical compositions, uses and methods of making the same. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, such as beta-lactamase inhibitors (BLIs).

Description

Boronic acid derivatives and their therapeutic use
Background
FIELD
The present application relates to the fields of chemistry and medicine. More particularly, the present application relates to boronic acid antimicrobial compounds, compositions, their preparation and their use as therapeutic agents.
Description of the related Art
Antibiotics have been an effective tool for the treatment of infectious diseases in the past half century. Bacterial infections are almost completely controlled in developed countries from the development of antibiotic treatments to the end of the eighties of the twentieth century. However, against the pressure to use antibiotics, a variety of resistance mechanisms have become widespread and threaten the clinical utility of antibacterial therapy. The increase of antibiotic resistant strains has been particularly prevalent in major hospitals and care centers. The increased consequences of resistant strains include higher morbidity and mortality, longer patient hospitalization and increased treatment costs.
A variety of bacteria have evolved β -lactam deactivating enzymes, i.e., β -lactamases that are resistant to the efficacy of a variety of β -lactam antibiotics. Beta-lactamases can be classified into 4 classes based on their amino acid sequence, i.e., the Ambler class A, B, C and D. Enzymes in class A, C and class D include the active site serine beta-lactamases, and the less frequently encountered class B enzymes are Zn-dependent. These enzymes catalyze the chemical degradation of β -lactam antibiotics, rendering them inactive. Some beta-lactamases are transferable within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multiply resistant strains severely limited the availability of beta-lactam therapeutic options.
The increase in class D β -lactamase-expressing bacterial strains, such as Acinetobacter baumannii, has become a emerging threat of multi-drug resistance. Acinetobacter baumannii strains express A, C and class D beta-lactamase. Class D beta-lactamases, e.g. beta-lactam antibiotics of the OXA family for the destruction of carbapenem forms (e.g. imipenem, Merck's)
Figure BDA0003510565690000011
Active carbapenem component of (e.g., Montefour, k. et al. crit. care Nurse 2008, 28, 15; perez, f. et al, Expert rev, anti infection, ther, 2008, 6, 269; bou, G.; Martinez-Beltran, J.Antimicrob. ingredients chemither.2000, 40, 428.2006, 50, 2280; bou, g, et al, j.animicrob.ingredients chemither.2000, 44, 1556). This poses an urgent threat to the effective use of such drugs in the treatment and prevention of bacterial infections. In fact, the number of classified serine-based beta-lactamases has proliferated from less than 10 to over 300 variants in the seventies of the twentieth century. These problems have prompted the development of five "generations" of cephalosporins. When initially administered to clinical practice, broad spectrum cephalosporins resist hydrolysis by the prevalent class A beta-lactamases, TEM-1 and SHV-1. However, the development of resistant strains due to the evolution of single amino acid substitutions in TEM-1 and SHV-1 led to the emergence of a broad spectrum of beta-lactamase (ESBL) phenotypes.
Recently, new beta-lactamases have been developed which hydrolyze carbapenem-based antimicrobials including imipenem, biapenem, doripenem, meropenem and ertapenem, as well as other beta-lactam antibiotics. These carbapenemases belong to the molecules A, B and class D. The KPC type of carbapenemases in class A are mainly in Klebsiella pneumoniae (Klebsiella pneumoniae), however, it is now reported in other Enterobacter (Enterobacteriaceae), Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Acinetobacter baumannii. KPC carbapenemases were first described in 1996 in north carolina, but since then widely spread in the united states. Especially in the new york city area, where several reports of spread in major hospitals and patient morbidity have been reported, has become problematic. These enzymes have also been recently reported in france, greece, sweden, uk, and a sudden outbreak in germany has been recently reported. Treatment of resistant strains with carbapenems may be associated with poor outcomes.
Zinc dependent class B metallo-beta-lactamases are mainly represented by VIM, IMP and NDM types. IMP-producing and VIM-producing klebsiella pneumoniae were first observed in japan in the nineties of the twentieth century and south europe in 2001, respectively. IMP positive strains remain frequent in japan and they also cause hospital outbreaks in china and australia. However, the spread of IMP producing enterobacteria in the rest of the world appears to be somewhat limited. Enterobacteria producing VIM can be frequently isolated in mediterranean countries to reach the greek infection rate. Isolation of VIM producing strains in northern europe and the united states remained low. In stark contrast, the nature of NDM-producing klebsiella pneumoniae isolates is rapidly spreading from their centers (indian subcontinent) to western europe, north america, australia and far east. Furthermore, the NDM gene has spread to a variety of species other than klebsiella pneumoniae.
The plasmid-expressed class D carbapenemases are of the OXA-48 type. In the first time in the 2001 ear, Klebsiella pneumoniae producing OXA-48 was detected. The middle east and north africa remain the major centers of infection. However, recent isolation of organisms producing type OXA-48 in india, senegal and argentina has shown the potential for global expansion. Isolation of OXA-48 in bacteria other than klebsiella pneumoniae underscores the potential for OXA-48 diffusion.
Treatment of strains producing any of these carbapenemases with carbapenems may be associated with poor outcomes.
Another mechanism of beta-lactamase-mediated resistance to carbapenems involves a combination of osmotic or efflux mechanisms coupled with the overproduction of beta-lactamases. One example is that loss of porin associated with overproduction of ampC beta-lactamases leads to resistance to imipenem in pseudomonas aeruginosa. Overexpression of the efflux pump in combination with overproduction of the ampC β -lactamase may also result in resistance to carbapenems such as meropenem.
Accordingly, there is a need for improved therapies using beta-lactamase inhibitors (BLIs).
Disclosure of Invention
Some embodiments described herein relate to a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:
Figure BDA0003510565690000031
and a pharmaceutically acceptable excipient; and further comprising an additional agent, wherein the additional agent may be ceftolozane or sulbactam.
Other embodiments described herein relate to pharmaceutical compositions comprising a therapeutically effective amount of a compound having the structure:
Figure BDA0003510565690000032
and a pharmaceutically acceptable excipient; and further comprising an additional agent, wherein the additional agent may be cefditorel (cefaderocol).
In some embodiments, the pharmaceutically acceptable salt may be an alkali metal salt or an ammonium salt. In some embodiments, the sodium salt may be
Figure BDA0003510565690000041
Figure BDA0003510565690000042
In other embodiments, the sodium salt may be
Figure BDA0003510565690000043
Some embodiments described herein relate to a method of treating a bacterial infection comprising administering to a subject a pharmaceutical composition comprising a compound having the structure:
Figure BDA0003510565690000044
some embodiments described herein relate to a method of treating a bacterial infection comprising administering to an individual a pharmaceutical composition comprising a compound having the structure:
Figure BDA0003510565690000045
in some embodiments, the infection may comprise a bacterium selected from the group consisting of: pseudomonas acidovorans (Pseudomonas acidophilus), Pseudomonas alcaligenes (Pseudomonas alcaligenes), Pseudomonas putida (Pseudomonas putida), Burkholderia cepacia (Burkholderia cepacia), Aeromonas hydrophila (Aeromonas hydrophila), Francisella tularensis (Francisella tularensis), Morganella morganii (Morganella morganii), Proteus mirabilis (Proteus mirabilis), Proteus vulgaris (Providella vulgaris), Providencia alcaliensis (Providelia californica), Providencia retta (Providencia verticillaceae), Bordetella pertussis (Bordetella), Bordetella pertussis multocida (Bordetella pertussis), Bordetella pertussis (Bordetella), Bordetella pertussis multocida (Bordetella pertussis multocida), Bordetella pertussis multocida (Bordetella), Bordetella pertussis mularia), Bordetella (Bordetella), Bordetella pertussis mularia), Bordetella sp Borrelia burgdorferi (Borrelia burgdorferi), Corynebacterium (Kingella), Gardnerella vaginalis (Gardnerella vaginalis), Bacteroides (Bacteroides distasonis), Bacteroides 3452A homologous group (Bacteroides 3452A homology group), Clostridium difficile (Clostridium difficile), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium avium (Mycobacterium avium), Mycobacterium intracellulare (Mycobacterium intracellulare), Mycobacterium leprae (Mycobacterium leprae), Corynebacterium diphtheriae (Corynebacterium diphyteriae), Corynebacterium ulcerous (Corynebacterium pneumoniae), Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus faecalis (Staphylococcus epidermidis), Staphylococcus aureus (Staphylococcus epidermidis) Staphylococcus hemolyticus (Staphylococcus haemolyticus), Staphylococcus hominis (Staphylococcus hominis), and Staphylococcus sacchari (Staphylococcus saccharolyticus).
In other embodiments, the infection may comprise a bacterium selected from the group consisting of: pseudomonas aeruginosa (Pseudomonas aeruginosa), Pseudomonas fluorescens (Pseudomonas fluorescens), Stenotrophomonas maltophilia), Escherichia coli (Escherichia coli), Citrobacter freundii (Citrobacter freundii), Salmonella typhimurium (Salmonella typhimurium), Salmonella typhi (Salmonella typhi), Salmonella paratyphi (Salmonella paratyphi), Salmonella enteritidis (Salmonella enteritidis), Shigella dysenteriae (Shigella dysseniae), Shigella flexneri (Shigella flexneri), Shigella sonnei (Shigella flexneri), Shigella sonneri (Shigella sonneri), Shigella sonnei (Shigella sonnei), Salmonella sonnei (Shigella sonnei), Enterobacter cloacae (Enterobacter clausii), Enterobacter aerogenes (Enterobacter pneumoniae), Escherichia coli (Klebsiella pneumoniae), Yersinia enterocolibacillus (Yersinia enterocolitica), Escherichia coli (Yersinia Acinetobacter coli), Escherichia coli (Yersinia colibacillus acidogenic bacteria (Yersinia), Escherichia coli colibacillus acidogenic bacteria (Yersinia), Escherichia coli (Yersinia), Yersinia colibacillus coli (Yersinia), Enterobacter lactis), Escherichia coli (Yersinia), Escherichia coli colibacillus coli (Yersinia), Yersinia acidum acidicinolytica), Yersinia acidum (Yersinia), Yersinia acidici, Yersinia intermedia (Yersinia intermedia), Haemophilus influenzae (Haemophilus influenzae), Haemophilus parainfluenzae (Haemophilus parainfluenzae), Haemophilus haemolyticus (Haemophilus haemolyticus), Haemophilus parahaemolyticus (Haemophilus parahaemolyticus), Helicobacter pylori (Helicobacter pylori), Campylobacter foetus (Campylobacter focus), Campylobacter jejuni (Campylobacter jejuni), Campylobacter coli (Campylobacter coli), Vibrio cholerae (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), legionella pneumophila (Legionella pneumoniae), Listeria monocytogenes (Listeria monocytogenes), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Neisseria meningitidis (Neisseria meningitidis), Moraxella (Moraxella), Bacteroides fragilis (Bacteroides fragilis), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides ovatus (Bacteroides ovanus), Bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), Bacteroides monoides (Bacteroides uniflora), Bacteroides egeria exhi (Bacteroides degermoides gerthiii) and Bacteroides visceral sporangius (Bacteroides splanchnicus).
In some specific embodiments, the infection may comprise pseudomonas aeruginosa bacteria. In other embodiments, the infection may comprise acinetobacter baumannii bacteria.
Some embodiments described herein relate to a method of treating a bacterial infection comprising administering to an individual in need thereof a compound having the structure:
Figure BDA0003510565690000061
and other agents, wherein the other agents may be ceftolozane or sulbactam.
In some embodiments, the compound and the other agent may be administered simultaneously. In other embodiments, the compound and the other agent may be administered sequentially.
In some specific embodiments, the infection may comprise pseudomonas aeruginosa bacteria. In other embodiments, the infection may comprise acinetobacter baumannii bacteria.
Brief Description of Drawings
Figure 1A shows the minimal inhibitory concentration profile of compound 1 combination against carbapenem-resistant acinetobacter baumannii.
Figure 1B shows the minimal inhibitory concentration profile of the compound 1 combination against carbapenem-resistant acinetobacter baumannii with defined carbapenemases.
Figure 2 shows the minimum inhibitory concentration profile of meropenem, cefepime and ceftaroazane alone and together with 8 μ g/mL of compound 1 against carbapenem-resistant enterobacteria.
The figure shows data for an enterobacterium that lacks carbapenem-resistant metallo-beta-lactamases (no MBL; N ═ 264) and has carbapenem-resistant metallo-beta-lactamases (MBL; N ═ 145).
Detailed Description
Compound 1
Some embodiments provided herein include compounds 1,
Figure BDA0003510565690000071
or a pharmaceutically acceptable salt thereof, which contains a boronic acid moiety. Compound 1 may act as an antimicrobial and/or an enhancer for an antimicrobial.
In some embodiments, the pharmaceutically acceptable salt is selected from an alkali metal salt or an ammonium salt. In one embodiment, the pharmaceutically acceptable salt is a sodium salt, including the disodium salt.
In some embodiments, compound 1 described herein can be converted to or exist in equilibrium with an alternative form due to the facile exchange of boron esters. Thus, in some embodiments, compound 1 described herein may be present in combination with one or more of these forms. For example, as shown below, compound 1 disclosed herein may be present as a cyclic boronic ester monoester having the structure of compound 1-a, depending on the medium. An exemplary equilibrium equation between compound 1 and compound 1-a in an aqueous medium is shown below:
Figure BDA0003510565690000081
definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. Unless otherwise indicated, if there are multiple definitions for a term herein, the definition in this section controls. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise stated, the use of "or" and "means" and/or ". Furthermore, the term "including" and other forms of use are not limited, such as "including", "includes" and "including". As used in this specification, the terms "comprises/comprising" and "comprises/comprising" are to be interpreted as having an open-ended meaning, whether in transitional phrases or in the body of a claim. That is, these terms are to be construed as synonymous with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include other steps. The term "comprising" when used in the context of a compound, composition or device means that the compound, composition or device includes at least the recited features or components, but may also include other features or components.
An "individual", as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird (e.g., chicken), as well as any other vertebrate or invertebrate animal.
The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates (including apes (chimpanzees, apes, monkeys) and humans), cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described in the following documents: e.g., Gilman et al (eds) (1990); goodman and Gilman: the Pharmacological Basis of Therapeutics, 8 th edition, Pergamon Press.
The therapeutic effect alleviates to some extent one or more symptoms of the disease or condition and includes a cure for the disease or condition. "cure" means to eliminate the symptoms of a disease or condition; however, even after healing has occurred, there may be some long-term or permanent effects (e.g., extensive tissue damage).
As used herein, "treatment" or "treating" refers to administering a compound or pharmaceutical composition to an individual for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of an individual who does not yet exhibit symptoms of a disease or condition, but who is predisposed to, or otherwise at risk of, a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to administering a treatment to an individual already suffering from a disease or condition.
The compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic form. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.
The skilled artisan will recognize that the structures described herein may be resonance forms or tautomers of the compounds, which may be clearly represented by other chemical structures, even kinetically; the skilled artisan recognizes that such structures may represent only a small portion of a sample of such compounds. Although such resonance forms or tautomers are not shown herein, such compounds are considered to be within the scope of the structures described.
Isotopes may be present in the compounds. Each chemical element represented in the structure of the compound may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. The hydrogen atom may be present at any position of the compound and may be any isotope of hydrogen including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, unless the context clearly dictates otherwise, the compounds referred to herein encompass all possible isotopic forms.
"solvate" refers to a compound formed by the interaction of a solvent with a compound, metabolite, or salt thereof described herein. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.
The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of a compound and is not biologically or otherwise undesirable for use in a medicament. In many cases, the compounds herein are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases. Inorganic bases from which salts can be obtained include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be obtained include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art as described in WO87/05297 to Johnston et al, published on 9/11 1987, which is incorporated herein by reference in its entirety.
Some examples of pharmaceutically acceptable base addition salts of compound 1 or compound 1-a disclosed herein have the structure of compound 1 'or compound 1-a':
Figure BDA0003510565690000101
Figure BDA0003510565690000102
wherein
Figure BDA0003510565690000103
And each of R may be independently selected from an alkali metal cation or an ammonium cation (NH)4 +)。
Some examples of pharmaceutically acceptable base addition salts of compound 1 or compound 1-a disclosed herein have the structure of compound 1 "or compound 1-a":
Figure BDA0003510565690000111
Figure BDA0003510565690000112
wherein each R may be independently selected from an alkali metal cation or an ammonium cation (NH)4 +)。
In some embodiments, the salt of compound 1 has the structure
Figure BDA0003510565690000113
In other embodiments, the salt of compound 1 has the structure
Figure BDA0003510565690000114
In some embodiments, the salt of compound 1-a has the structure
Figure BDA0003510565690000115
In other embodiments, the salt of compound 1-a has the structure
Figure BDA0003510565690000116
Preparation method
Compound 1 and compound 1-a can be synthesized by the methods described in example 1, by modifying the methods, or using the methods disclosed in international patent publications nos. WO 2018/005662 and WO 2018/075084, the entire contents of which are incorporated herein by reference. Means for modifying the process known to those skilled in the art include, temperature, solvents, reagents, and the like. Generally, in any of the methods of making the compounds disclosed herein, it is necessary and/or desirable to protect sensitive or reactive groups of any molecule involved. This can be achieved by conventional protecting groups, such as those described below: protective Groups in Organic Chemistry (edited by J.F.W.McOmie, Plenum Press, 1973); and p.g.m.green, t.w.wutts, Protecting Groups in Organic Synthesis (3 rd edition) Wiley, New York (1999), both hereby incorporated by reference in their entireties. At a convenient subsequent stage, the protecting group may be removed using methods known in the art. Synthetic chemical transformations for synthesizing suitable compounds are known in the art and include, for example, those described below: larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or l.paquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both hereby incorporated by reference in their entirety. The approaches shown and described herein are illustrative only and are not intended to, nor should they be construed to, limit the scope of the claims in any way. One skilled in the art should be able to recognize modifications to the disclosed syntheses and may devise alternative routes based on the disclosure herein; all such modifications and alternative approaches are intended to be within the scope of the claims.
Administration and pharmaceutical compositions
Compound 1 or compound 1-a in combination with other agents is administered at a therapeutically effective dose. In some embodiments, the other agent may be ceftolozane or sulbactam. In some embodiments, the other agent may be cefditorel. However, for the compounds and other agents described herein to remain optimized for human dosage levels, in general, the daily dose may be from about 0.25mg/kg body weight to about 120mg/kg body weight or more, from about 0.5mg/kg body weight or less to about 70mg/kg body weight, from about 1.0mg/kg body weight to about 50mg/kg body weight, or from about 1.5mg/kg body weight to about 10mg/kg body weight. Thus, for administration to a 70kg human, the dosage range may be from about 17mg per day to about 8000mg per day, from about 35mg or less per day to about 7000mg or more per day, from about 70mg per day to about 6000mg per day, from about 100mg per day to about 5000mg per day, or from about 200mg per day to about 3000mg per day. The amounts of active compound and other agents administered will, of course, depend on the individual and disease state being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician.
The combination of compound 1 or compound 1-a and other agents disclosed herein, or pharmaceutically acceptable salts thereof, can be administered by any acceptable mode of administration of agents with similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
The combination of compound 1 or compound 1-a with other agents useful as described herein can be formulated into pharmaceutical compositions for the treatment of these conditions. In some embodiments, compound 1 or compound 1-a and the other agent can be formulated in separate pharmaceutical compositions, while in other embodiments, compound 1 or compound 1-a and the other agent can be formulated in the same pharmaceutical composition. Standard pharmaceutical formulation techniques are used, such as those disclosed below: the Science and Practice of Pharmacy, 21 st edition, Lippincott Williams & Wilkins (2005), by Remington, is incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
Some embodiments include compositions comprising a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as those commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al (eds.) (1990); goodman and Gilman: the Pharmacological Basis of Therapeutics, 8 th edition, Pergamon Press, which is incorporated herein by reference in its entirety.
Some examples of substances that may be used as pharmaceutically acceptable carriers or components thereof are: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting reagents and stabilizing agents; an antioxidant; a preservative; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of pharmaceutically acceptable carrier to be used in combination with the subject compound and other agent is essentially determined by the mode of administration of the compound and other agent.
The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition that comprises an amount of a compound suitable for administration to an animal (preferably a mammalian subject), and a single dose, according to good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is to be administered once per day or once per course of treatment. Such dosage forms are contemplated to be administered once, twice, three times or more daily, and may be administered as an infusion over a period of time (e.g., about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be administered more than once during a course of treatment, although single administrations are not specifically excluded. The skilled artisan will recognize that the formulation is not specifically contemplated for the entire course of treatment, and such decisions are left to the skilled artisan in the field of treatment, rather than the skilled artisan in the formulation field.
In some embodiments, compound 1 or compound 1-a and other agents disclosed herein can be formulated in a single unit dosage form suitable for administration to an individual in need thereof. In other embodiments, compound 1 or compound 1-a and other agents disclosed herein can be formulated in separate unit dosage forms.
The above-described useful compositions may be in a variety of suitable forms for a variety of routes of administration, e.g., for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. The skilled artisan will recognize that oral and nasal compositions include compositions that are administered by inhalation and are obtained using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be employed. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, co-solvents, surfactants, and encapsulating substances. Optional pharmaceutically active materials may be included which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide the actual amount of material corresponding to administration per unit dose of the compound. Techniques and compositions for obtaining dosage forms for use in the methods described herein are described in the following references, all of which are incorporated herein by reference: modern pharmaceuticals, 4 th edition, chapters 9 and 10 (Banker and Rhodes eds., 2002); lieberman et al, Pharmaceutical Dosage Forms: tablets (1989); and Ansel, Introduction to pharmaceutical delivery Forms 8 th edition (2004).
A variety of oral dosage forms may be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets may be compressed, tablet milled, enteric coated, sugar coated, film coated or multiple compressed and contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules, which contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and flavoring agents.
Pharmaceutically acceptable carriers suitable for use in preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrating agents, such as starch, alginic acid and crosslinked carboxymethyl cellulose; lubricants, for example, magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants, such as FD & C dyes, may be added for appearance. Sweetening agents and flavoring agents are useful adjuvants for chewable tablets, such as aspartame, saccharin, menthol, peppermint, and fruit flavors. Capsules typically contain one or more of the solid diluents disclosed above. The choice of carrier component depends on secondary considerations such as taste, cost and storage stability, which are not critical and readily available to the skilled person.
Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for use in preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspending agents, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, gum tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweetening agents, flavoring agents and coloring agents as disclosed above.
Such compositions may also be coated by conventional means, typically using a pH-dependent or time-dependent coating, such that the subject compound is released in the vicinity of the desired topical application in the gastrointestinal tract, or at a different time to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, acrylic coatings, waxes, and shellac.
The compositions described herein may optionally include other pharmaceutical actives.
Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more soluble filler materials, such as sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.
Liquid compositions formulated for topical ocular application are formulated such that they can be topically applied to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may not result in optimal comfort. In cases where comfort cannot be maximized, the liquid should be formulated so that it is tolerable to the patient for topical ocular application. Additionally, ophthalmically acceptable liquids should be packaged for single use, or contain preservatives to prevent contamination over multiple uses.
For ophthalmic applications, solutions or medicaments are generally prepared using physiological saline solution as the primary vehicle. The ocular solution should preferably be kept at a comfortable pH with a suitable buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Likewise, a variety of useful vehicles may also be used in the ophthalmic formulations disclosed herein. Such vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.
Tonicity adjusting agents may be added as needed or convenient. They include, but are not limited to, salts (especially sodium chloride, potassium chloride), mannitol and glycerol, or any other suitable ophthalmically acceptable tonicity modifier.
A variety of buffers and methods for adjusting pH may be used, so long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH is from 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations can be adjusted with acids or bases as needed.
Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene.
Other excipient components that may be included in the ophthalmic formulation are chelating agents. A useful chelating agent is edetate disodium, but other chelating agents may be substituted for or combined with it.
For topical application, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may typically include a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.
For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent (e.g., saline or dextrose solution). Suitable excipients may also be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients present in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as glucose, mannitol, and dextran. Other acceptable excipients are described in the following: powell et al, Complex of Excipients for specialized Formulations, PDA J Pharm Sci and Tech 1998, 52238-: current uses and Future directives, PDA J Pharm Sci and Tech 2011, 65287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to obtain a bacteria-inhibiting or fungi-inhibiting solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
The compositions for intravenous administration may be provided to the caregiver in the form of one or more solids which may be reconstituted with a suitable diluent, such as sterile water, saline, or aqueous dextrose, immediately prior to administration. In other embodiments, the composition is provided in the form of a solution ready for parenteral administration. In still other embodiments, the composition is provided in a solution that requires further dilution prior to administration. In embodiments that include the administration of a combination of a compound described herein with other agents, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.
The actual dosage of the active compounds described herein depends on the particular compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of the skilled person.
Method of treatment
Some embodiments of the invention include methods of treating bacterial infections with compound 1 or compound 1a and other agents and compositions comprising compound 1 or 1a and other agents described herein. Some embodiments include methods of treating bacterial infections with compound 1 or compound 1a in combination with other agents selected from sulbactam, ceftaroline and cefditorel. Some methods comprise administering to an individual in need thereof a combination described herein. In some embodiments, the subject may be an animal, such as a mammal (including a human). In some embodiments, the bacterial infection comprises a bacterium described herein. It will be appreciated from the above that methods of treating bacterial infections include methods of preventing bacterial infections in individuals at risk of bacterial infections.
In some embodiments, the individual is a human.
Some embodiments include co-administration of compound 1 or compound 1-a with other agents. By "co-administration" is meant that two or more agents may be present in the bloodstream of a patient at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, the combined administration is achieved by combining the agents in a single dosage form. In another such embodiment, the combined administration is achieved by combining the agents in separate dosage forms. In other embodiments, the agents are administered sequentially. In one embodiment, the agents are administered by the same route, e.g., orally or intravenously. In another embodiment, the agents are administered by different routes, e.g., one is orally and the other is intravenously (i.v.).
In some embodiments, the additional agent is selected from ceftolozane and sulbactam. In some embodiments, the other agent is cefditorel.
Some specific embodiments include a combination of compound 1 or a pharmaceutically acceptable salt thereof and sulbactam. Other specific embodiments include a combination of compound 1-a or a pharmaceutically acceptable salt thereof and sulbactam. Some specific embodiments include a combination of compound 1 or a pharmaceutically acceptable salt thereof and ceftaroline. Other specific embodiments include a combination of compound 1-a or a pharmaceutically acceptable salt thereof and ceftaroline.
Some specific embodiments include a combination of compound 1 or a pharmaceutically acceptable salt thereof and ceftizol. Other specific embodiments include a combination of compound 1-a or a pharmaceutically acceptable salt thereof and ceftizol.
The combination of compound 1 or compound 1-a with other agents may also include a second other agent. Examples of other second agents include antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and antiallergic agents. In some embodiments, the second additional agent comprises a beta-lactam. Examples of such beta-lactams include amoxicillin, ampicillin (e.g., pivampicillin, patatin, methicillin, phthalacillin), epicillin, carbenicillin (cainacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin (pimecrillin), sulbenicillin, benzylpenicillin (G), cloxacillin, benzathine benzylpenicillin, procarbazycillin, Doxil, penacilin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, fenpicillin, cloxacillin (e.g., dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, cefozoperin, cefazolin, acetonitrile, methicillin, mefuracilin, mefenacil, mefenacin, pencillin, mefenacin, mezopenim, mefenacin, cefepimecillin, cefepimembrin, pencillin, cefepimembrin, cefazolin, mefenapanipenemine, mefene, mefenapanipenemine, mefenocillin, mefenozilin, mefenapanipenemine, mefenethixenine, mefene, mefenethixenine, mefene, me, Cefadroxil, cephalexin, cefalexin, cefalon, cefloram, ceftiofur, ceftriazine, cefuroxime, cefazedone, cefradine, cefoxadin, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefdinir, cefbuperazone, cefuroxime, ceftizoxime, cefoxitin, cefotetan, cefmetazole, chlorocephem, cefixime, ceftazidime, ceftriaxone, cefcapene, cefixime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefdinir, cefodizime, cefoperazone, cefotaxime, cefepime, cefpodoxime, cefsulodin, cefteram, cefobutazone, cefotaxime, ceftizoxime, flomox, cefepime, cefazolin, cefozopran, cefotaxime, Cefpirome, cefquinome, cefpiral, ceftaroline, ceftiofur, cefquinome, cefotaxime, aztreonam, tigemonam and carumonam.
Indications of
Compounds and compositions comprising the compounds described herein are useful for treating bacterial infections. Bacterial infections that can be treated with the compounds, compositions, and methods described herein can include a broad spectrum of bacteria. Examples of organisms include gram-positive, gram-negative, aerobic and anaerobic bacteria, such as staphylococci (Staphylococcus), lactobacilli (Lactobacillus), streptococci (Streptococcus), Sarcina (Sarcina), Escherichia (Escherichia), Enterobacter (Enterobacter), Klebsiella (Klebsiella), Pseudomonas (Pseudomonas), Acinetobacter (Acinetobacter), Mycobacterium (Mycobacterium), Proteus (Proteus), Campylobacter (Campylobacter), Citrobacter (Citrobacter), neisseria (Nisseria), bacillus (bacillus), Bacteroides (Bacteroides), Peptococcus (Peptococcus), Clostridium (Clostridium), Salmonella (Salmonella), Shigella (gella), Serratia (sarrra), Haemophilus (Haemophilus), and other organisms.
Further examples of bacterial infections include Pseudomonas aeruginosa (Pseudomonas aeruginosa), Pseudomonas fluorescens (Pseudomonas fluorescens), Pseudomonas acidovorans (Pseudomonas acidovorans), Pseudomonas alcaligenes (Pseudomonas alcaligenes), Pseudomonas putida (Pseudomonas putida), Stenotrophomonas maltophilia (Stenotrophora), Burkholderia cepacia (Burkholderia cepacia), Aeromonas hydrophila (Aeromonas hydrophila), Escherichia coli (Escherichia coli), Citrobacter freundii (Citrobacter uniundiii), Salmonella typhimurium (Salmonella typhimurium), Salmonella typhi (Salmonella typhimurium), Salmonella paratyphi (Salmonella typhimurium), Salmonella typhimurium (Shigella), Shigella dysenteriae (Shigella Enterobacter), Salmonella enterica (Escherichia coli), Salmonella enterica (Escherichia coli), Escherichia coli (Salmonella enterica), Escherichia coli (Escherichia coli), Shigella Enterobacter coli (Escherichia coli), Shigella lactis (Escherichia coli), Escherichia coli (Shigella lactis) Serratia marcescens (Serratia marcescens), Francisella tularensis (Francisella tularensis), Morganella morganii (Morganella morganii), Proteus mirabilis (Proteus mirabilis), Proteus vulgaris (Proteus vulgaris), Providence communis (Providence alcaligenes), Providence Providencia (Providence repgeri), Providence Providencia stuartii (Providence stuartii), Acinetobacter baumannii (Acinetobacter baumannii), Acinetobacter calcoaceticus (Acinetobacter calcoaceticus), Acinetobacter haemolyticus (Acinetobacter haeformis), Yersinia enterocolitica (Yersinia Yersinia), Yersinia pestis (Bordetella), Bordetella parahaemolytica (Bordetella flava), Bordetella parahaemolytica (Bordetella parahaemophila), Bordetella parahaemophilus (Bordetella), Bordetella pertussis parahaemophilus (Bordetella), Bordetella parahaemophilus (Bordetella) and Bordetella parahaemophilus, Haemophilus haemolyticus (Haemophilus haemolyticus), Haemophilus parahaemolyticus (Haemophilus parahaemolyticus), Haemophilus ducreyi (Haemophilus ducreyi), Pasteurella multocida (Pasteurella multocida), Pasteurella haemolyticus (Pasteurella haemolytica), Branhamella catarrhalis (Branhamella catarrhalis), Helicobacter pylori (Helicobacter pylori), Campylobacter foetidulus (Campylobacter fetalis), Campylobacter jejuni (Campylobacter jejuni), Campylobacter coli (Campylobacter coli), Bordetella Borrelia (Borrelia burgdorferi), Vibrio cholerae (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), Salmonella parahaemolyticus (Salmonella), Salmonella choleraesuis), Salmonella vaginalis (Salmonella), Salmonella choleraesuis (Legiononii), Salmonella cholerae (Salmonella), Salmonella cholera meningitidis (Legionna), Salmonella cholera (Salmonella), Salmonella cholerae (Salmonella), Salmonella cholera (Salmonella), Salmonella, and combinations thereof, Salmonella, and combinations of, and combinations thereof, Salmonella, and combinations thereof, and, Bacteroides 3452A homologous group (Bacteroides 3452A homology group), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides ovatus (Bacteroides ovatus), Bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), Bacteroides monoides (Bacteroides uniflora), Bacteroides exxoides (Bacteroides eggertii), Bacteroides viscera Bacteroides (Bacteroides splanchnochloris), Clostridium difficile (Clostridium difficile), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium avium (Mycobacterium avium), Mycobacterium intracellulare (Mycobacterium intracellulare), Mycobacterium leporicus (Mycobacterium tuberculosis), Corynebacterium diphtheriae (Corynebacterium diphtheriae), Streptococcus ulceroides (Streptococcus faecalis), Streptococcus faecalis (Staphylococcus aureus), Streptococcus faecalis (Streptococcus faecalis), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus faecalis), Streptococcus (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus (Streptococcus faecalis (Streptococcus), Streptococcus (Streptococcus faecalis (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus faecalis (Streptococcus), Streptococcus (Streptococcus), Streptococcus) and Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus) and Streptococcus) are strain (Streptococcus) and Streptococcus (Streptococcus) are, Streptococcus (Streptococcus) are strain (Streptococcus) and Streptococcus (Streptococcus) including Bacillus faecalis), Staphylococcus (Streptococcus), Staphylococcus (Streptococcus) and Streptococcus (Streptococcus) are, Streptococcus (Streptococcus) and Streptococcus (Streptococcus) are strain (Streptococcus) are strain (Streptococcus) and Streptococcus) are strain (Streptococcus) are, Staphylococcus intermedius (Staphylococcus intermedius), Staphylococcus suis subsp.hyicus (Staphylococcus hyicus), Staphylococcus haemolyticus (Staphylococcus haemolyticus), Staphylococcus hominis (Staphylococcus hominis), or Staphylococcus saccharolyticus (Staphylococcus saccharolyticus).
Some preferred embodiments relate to the treatment of infections comprising acinetobacter baumannii bacteria. Other preferred embodiments relate to the treatment of infections comprising pseudomonas aeruginosa bacteria.
To further illustrate the invention, the following examples are included. Of course, these examples should not be construed as particularly limiting the invention. Variations of these embodiments that fall within the scope of the claims are within the skill of those in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader should appreciate that those skilled in the art, with the benefit of this disclosure and skill in the art, will be able to make and use the invention without the need for exhaustive examples. The invention will be further described in the following examples, which are intended for illustrative purposes only and should not be taken as limiting.
Examples
General procedure
The materials used to prepare the cyclic boronic acid ester derivatives described herein can be prepared by known methods or are commercially available. It will be apparent to the skilled artisan that the methods of preparation of the precursors and functional groups associated with the compounds claimed herein are generally described in the literature, including, for example, the procedures described in U.S. patent No. 7,271,186, international patent publication No. WO 2009/064414, and international patent publication No. WO 2018/005662, each of which is incorporated herein by reference in its entirety. In these reactions, variants can also be used, which are known per se to the person skilled in the art, but are not mentioned in more detail. The skilled person, having access to the literature and the present disclosure, is sufficient to prepare any of the compounds.
It will be appreciated that those skilled in the art of organic chemistry can readily perform these operations without further guidance, that is, performing these operations is well within the knowledge and practice of the skilled artisan. These include the reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution (including both electrophilic and nucleophilic), etherification, esterification, saponification, and the like. These operations are discussed in standard text, such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in its entirety), and the like.
The skilled person will readily recognise that it is desirable to carry out certain reactions when other functional groups are masked or protected in the molecule, thereby avoiding any undesirable side reactions and/or increasing the reaction yield. Generally, the skilled person utilizes protecting groups to achieve such improved yields or to avoid undesired reactions. These reactions can be found in the literature and are well within the knowledge of the skilled person. Examples of a variety of these operations can be found, for example, in protective Groups in Organic Synthesis, 4 th edition, John Wiley & Sons (2007), both in t.greene and p.wuts, which are incorporated herein by reference in their entirety.
The following examples are provided for the guidance of the reader and represent preferred methods of preparing the exemplified compounds shown herein. These methods are not limiting and it is clear that other routes can be used to prepare these compounds. These methods specifically include solid phase chemistry, which includes combinatorial chemistry. The skilled worker is fully enabled to prepare these compounds according to the methods given in the literature and the present disclosure. The compound numbers used in the synthetic schemes described below are meant only for those specific schemes and should not be understood as being, or confused with, the same numbers used in other parts of the application.
The trademarks used herein are examples only and reflect exemplary materials used in the present invention. The skilled person will appreciate that many variations in manufacturing processes etc. are contemplated. Thus, these examples and the trademarks used therein are non-limiting and they are not intended to be limiting but merely to illustrate how a skilled person may choose to implement one or more embodiments of the present invention.
Example 1
5-fluoro-2-hydroxy-1 a,7 b-dihydro-1H-cyclopropa [ c][1,2]Benzoxaborole heterocycles Disodium salt of (benzoxaborinine) -4-carboxylic acid (Compound 1')
Figure BDA0003510565690000241
Step 1: synthesis of Compound 1A
Compound 1A was prepared from the Boc-tert-butyl ester intermediate (previously disclosed in WO 2015/179308) by TFA deprotection followed by isopropylidene protection as described in step 2 of example 1.
Step 2: synthesis of Compound 1B
To a solution of Compound 1A (16.0g, 58mmol, 1.0 equiv) in DMF (50mL) was added acrylic acid (6.0mL, 87mmol, 1.5 equiv.), TEA (24mL, 175mmol, 3 equiv.), Pd (OAc)2(651mg, 2.9mmol, 0.05 equiv.) and tri (o-tolyl) phosphine (1.77g, 5.8mmol, 0.1 equiv.). The reaction mixture was purged with nitrogen and stirred at 100 ℃ for 14 hours. The reaction mixture was concentrated to dryness, and the solid was washed with 0.2N HCl and DCM to give a yellow solid. The solid was washed with EtOAc and hexaneRecrystallization from alkane to give compound 1B as an off-white solid (8.2g, 53%).1H NMR(CD3OD，400MHz)：δ8.01(dd，1H)，7.78(d，J＝16.4Hz，1H)，7.00(dd，1H)，6.57(d，J＝16.0Hz，1H)，1.80(s，6H)。
And step 3: synthesis of Compound 1C
To a suspension of compound 1B (8.2g, 30.8mmol, 1.0 eq) in chloroform (300mL) at 0 ℃ was added liquid bromine (1.8mL, 35.4mmol, 1.15 eq) dropwise over 5 minutes. The reaction solution was stirred at 0 ℃ for 2 hours, and then concentrated under reduced pressure. The yellow solid obtained was crude compound 1C (14.7g), which was used in the next step without purification.
And 4, step 4: synthesis of Compound 1D
To a solution of compound 1C (14.7g, 30.8mmol, 1.0 equiv.) in DMF (35mL) at 0 deg.C was added triethylamine (8.6mL, 61.6mmol, 2.0 equiv.) dropwise over 2 minutes. The resulting reaction mixture was slowly warmed to room temperature and stirred for 8 hours. The reaction mixture was diluted with EtOAc and washed with 0.1N HCl and water. In the presence of Na2SO4After drying, the organic layer was concentrated and subjected to chromatography (hexane/EtOAc ═ 3/1 to 1/1) to give compound 4D (5.5g) as an off-white solid.1H NMR(CDCl3，400MHz)：δ8.20(dd，1H)，7.08(d，J＝8.0Hz，1H)，6.88(t，J＝8.2Hz，1H)，6.55(d，J＝8.0Hz，1H)，1.75(s，6H)。
And 5: synthesis of Compound 1E
Compound 1D (700mg, 2.3mmol, 1.0 equiv.), bis ((+) pinacolato) diboron (1.24g, 3.5mmol, 1.5 equiv.), PdCl2A mixture of (dppf) (188mg, 0.23mmol, 0.1 equiv) and KOAc (450mg, 4.6mmol, 2.0 equiv) in dioxane (15mL) was stirred under nitrogen at 60 ℃ for 2 hours. The reaction mixture was diluted with EtOAc and washed with 0.1N HCl and water. In the presence of Na2SO4After drying, the organic layer was concentrated and purified by column chromatography (hexane/EtOAc ═ 3/1 to 1/1) to give compound 1E (240mg, 26%) as a yellow solid. ESI-MS: [ M + H ]]+：401。
Step 6: synthesis of Compound 1F
To compound 1E (240mg, 0.6mmol, 1.0 equiv.) and Pd (OAc) at-10 deg.C2(6.8mg, 0.03mmol, 0.05 eq.) in THF (3mL) diazomethane (6mL, freshly prepared, ca. 0.2 to 0.3M in ether) was added slowly over 15 minutes. The solution was slowly warmed to room temperature and stirred for 2 hours, then concentrated to dryness. The resulting residue was purified by column chromatography (hexane/EtOAc ═ 3/1 to 1/1) to give compound 1F as a yellow oil (240mg, 99%). ESI-MS: [ M + H ]]+：415。
And 7: synthesis of Compound 1
A mixture of compound 1F (140mg, 0.34mmol, 1.0 equiv) in dioxane (1.5mL) and 3N NaOH (1.5mL) was stirred at room temperature for 1 hour, LCMS indicated disappearance of starting material. The reaction mixture was cooled to 0 deg.C, and TES (250mg), TFA (5mL) and i-BuB (OH) were added successively2(100 mg). The resulting yellow clear solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water/MeCN and purified by preparative HPLC (C18, acetonitrile and water as mobile phase, 0.1% TFA). The resulting solid (28mg) was dissolved in MeCN/water and adjusted to pH 9.5 with 1N NaOH (0.27 mL). After lyophilization, the crude sodium salt of compound 1 was dissolved in 1.0mL of water and acetone (8.0mL) was added dropwise. The resulting suspension was stirred at room temperature for 3 hours. The mixture was filtered and the solid was washed twice with acetone containing 10% water to give compound 1' (26mg) as an off-white solid.1H NMR(D2O，300MHz)：δ6.87(t，J＝7.2Hz，1H)，6.25(d，J＝8.4Hz，1H)，1.65–1.56(m，1H)，0.67–0.57(m，1H)，0.14–0.03(m，2H).F NMR(D2O，300MHz)：δ-124.9.ESI-MS：[M-H2O+H]+：205。
Example 2
The following examples also disclose embodiments of the present application in detail, which are not intended to limit the scope of the present disclosure in any way.
In this example, the in vitro activity of compound 1 in combination with several β -lactams, including sulbactam, meropenem, and ceftaroazan, was evaluated against Carbapenem (CR) -resistant clinical isolates of Acinetobacter Baumannii (AB) and Pseudomonas Aeruginosa (PA).
A total of 300 carbapenem-resistant acinetobacter baumannii (CRAB) (including a subset of 100 CRAB strains containing defined carbapenemases) and 1000 PA clinical isolates were tested by a reference broth microdilution method directed against β -lactam alone and in combination with compound 1(4 μ g/mL and 8 μ g/mL). From 2017 monitoring data (representative panel), 500 PA isolates were selected to represent a normal distribution of Meropenem (MER), ceftazidime-abamectin (CAZ-AVI), and ceftazidime-tazobactam (TOL-TAZ) resistance. In addition, 652PA isolates that were non-susceptible (NS) to MER (minimum inhibitory concentration (MIC), > 2. mu.g/mL) or TOL-TAZ (MIC, > 4. mu.g/mL), or resistant (R) to CAZ-AVI (MIC, > 8. mu.g/mL) (challenge group) were also tested.
The activity data of compound 1 in combination with sulbactam against a representative AB strain are shown in table 1. The data show that the combination of compound 1 with sulbactam improves the minimum inhibitory concentration of sulbactam alone against various AB strains.
Table 1: activity of Compound 1 in combination with Sulbactam (SUL) against representative strains (minimum inhibitory concentration (. mu.g/mL))
Figure BDA0003510565690000271
The Minimum Inhibitory Concentration (MIC) profiles for each combination of compound 1 for a representative group of PAs are provided in table 2. The combination of compound 1 and ceftaroline had excellent efficacy against a representative group of pseudomonas aeruginosa, reflecting the current MIC profile. The combination of compound 1 and ceftolozane was more effective than the combination of compound 1 and meropenem, and more effective on this group of isolates than the combination of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-abamectin (CAZ-AVI).
Table 2: compound 1 combinationsMinimum inhibitory concentration profile for a representative group of PAs (N500)
Figure BDA0003510565690000281
The MIC profiles for compound 1 in combination with various antibiotics for the pseudomonas aeruginosa challenge group are provided in table 3. The data show that the combination of compound 1 with ceftaroline has increased potency against the challenge group of PA. The combination of compound 1 with ceftolozane is more effective than the combination of compound 1 with meropenem, and more effective than the combination of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-abamectin (CAZ-AVI) against the challenge group enriched with ceftazidime-abamectin resistance and PA of the meropenem, caftolamine-tazobactam non-susceptible isolate.
Table 3: MIC profile for a representative group of compound 1(C1) combinations for PA (N ═ 500)
Figure BDA0003510565690000291
The activity of compound 1 in combination with Meropenem (MER), ceftaroline (TOL) and Sulbactam (SUL) is shown in table 4. The combination of compound 1 with various β -lactam antibiotics showed potent activity against CRAB and PA isolates as shown in table 4 and in fig. 1A and 1B. The combination of compound 1 with TOL showed activity against 300 CRABs (including 100 CRABs with defined CP) and against representative and challenge PA strains and restoration susceptibility (S) to TOL. TOL-Compound 1 was also more effective against TOL-TAZ and CAZ-AVI resistant isolates than TOL-TAZ and CAZ-AVI.
Table 4: activity of Compound 1 in combination with various beta-lactam antibiotics
Figure BDA0003510565690000301
Furthermore, 509 carbapenem-resistant enterobacteria were tested with meropenem, cefepime and ceftaroazane alone and in combination with 8 μ g/mL of compound 1. In addition, 262 strains of Pseudomonas aeruginosa with a meropenem MIC >2 μ g/mL were tested with meropenem, ceftarozole, cefepime and piperacillin alone and in combination with 8 μ g/mL of Compound 1.
The MIC profile of compound 1 in combination with meropenem, cefepime and ceftaroline alone or with 8 μ g/mL of compound 1 against carbapenem-resistant enterobacteria was tested. Compound 1 significantly increased the efficacy of all tested antibiotics and restored the efficacy of meropenem, cefepime and ceftaroazane against carbapenem-resistant enterobacteriaceae (figure 2).
Compound 1 also increased the proportion of susceptible pseudomonas aeruginosa. 262 strains of Pseudomonas aeruginosa having a meropenem MIC of greater than 2 μ g/mL were tested with meropenem, ceftolozane, cefepime and piperacillin alone and 8 μ g/mL of Compound 1. Table 5 shows the percent change in susceptible organisms at the breakpoint. Compound 1 increased the proportion of susceptible organisms for all tested agents.
Table 5: using Meropenem (MER), ceftaroline (TOL), cefepime (FEP) and piperacillin (PP) alone And 8 μ g/mL of Compound 1
Figure BDA0003510565690000311
Example 3
The following examples also disclose embodiments of the present application in detail, which are not intended to limit the scope of the present disclosure in any way.
In this example, the antibiotics meropenem, cefepime, ceftaroxime and cefditorel in combination with compound 1 at 4 μ g/ml and 8 μ g/ml were tested against a panel of 510 clinical isolates representing various types of carbapenem-resistant enterobacteriaceae (CRE). Cefditoren was tested under standard conditions in a medium rich in iron. The MIC90 for all antibiotics tested for this group was in the resistant range, and compound 1 shifted the MIC90 for all antibiotics (except for the ceftaroline tested for the metallo beta-lactamase MBL) to the susceptible range. The results are shown in table 6 and show that compound 1 significantly enhances the efficacy of these antibiotics against carbapenem-resistant enterobacteriaceae.
Table 6: compound 1 with Meropenem (MER), cefepime (FEP), ceftaroline (TOL) and cefditorel (DER) Combination of activities on various types of CRE (N-510)
Figure BDA0003510565690000321
Example 4
The following examples also disclose embodiments of the present application in detail, which are not intended to limit the scope of the present disclosure in any way.
In another experiment, groups of 503 clinical isolates of carbapenem-resistant A.baumannii were tested in combination with various antibiotics (meropenem, cefepime, ceftaroxime and cefditorel) and 4 μ g/ml and 8 μ g/ml of Compound 1. Compound 1 significantly enhanced the efficacy of meropenem and cefditoren against this highly resistant group of strains, shifting the MIC90 of both antibiotics to susceptible levels. Cefditoren was tested under standard conditions in a medium rich in iron. The results are presented in table 7.
Table 7: activity of Compound 1 in combination with various antibiotics against carbapenem-resistant A.baumannii (N-503)
Figure BDA0003510565690000331
While the disclosure has been described with reference to embodiments and examples, it will be understood that many and various modifications may be made without departing from the spirit of the disclosure. Accordingly, the present disclosure is to be limited only by the following claims.
All references cited herein, including patents, patent applications, articles, texts, etc., and the references cited herein, are hereby incorporated by reference in their entirety to the extent they are not fully incorporated by reference. In the event that one or more of the incorporated documents and similar materials differ or contradict the present application, including but not limited to defined terms, usage of terms, described techniques, etc., the present application controls.

Claims (23)

1. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:
Figure FDA0003510565680000011
or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable excipient; and further comprising an additional agent, wherein the additional agent is ceftolozane or sulbactam.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:
Figure FDA0003510565680000012
or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable excipient; and further comprising an additional agent, wherein the additional agent is cefditorel.
3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutically acceptable salt is an alkali metal or ammonium salt.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt is a sodium salt.
5. The pharmaceutical composition of any one of claims 1 to 4, wherein the sodium salt is
Figure FDA0003510565680000013
6. The pharmaceutical composition of any one of claims 1 to 4, wherein the sodium salt is
Figure FDA0003510565680000021
7. The pharmaceutical composition of any one of claims 1 to 4, wherein the sodium salt is
Figure FDA0003510565680000022
8. A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutical composition of any one of claims 1 to 7.
9. The method of claim 8, wherein the infection comprises a bacterium selected from the group consisting of: pseudomonas acidovorans (Pseudomonas acidophilus), Pseudomonas alcaligenes (Pseudomonas alcaligenes), Pseudomonas putida (Pseudomonas putida), Burkholderia cepacia (Burkholderia cepacia), Aeromonas hydrophila (Aeromonas hydrophila), Francisella tularensis (Francisella tularensis), Morganella morganii (Morganella morganii), Proteus mirabilis (Proteus mirabilis), Proteus vulgaris (Providella vulgaris), Providencia alcaliensis (Providelia californica), Providencia retta (Providencia verticillaceae), Bordetella pertussis (Bordetella), Bordetella pertussis multocida (Bordetella pertussis), Bordetella pertussis (Bordetella), Bordetella pertussis multocida (Bordetella pertussis multocida), Bordetella pertussis multocida (Bordetella), Bordetella pertussis mularia), Bordetella (Bordetella), Bordetella pertussis mularia), Bordetella sp Borrelia burgdorferi (Borrelia burgdorferi), Corynebacterium (Kingella), Gardnerella vaginalis (Gardnerella vaginalis), Bacteroides (Bacteroides distasonis), Bacteroides 3452A homologous group (Bacteroides 3452A homology group), Clostridium difficile (Clostridium difficile), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium avium (Mycobacterium avium), Mycobacterium intracellulare (Mycobacterium intracellulare), Mycobacterium leprae (Mycobacterium leprae), Corynebacterium diphtheriae (Corynebacterium diphyteriae), Corynebacterium ulcerous (Corynebacterium pneumoniae), Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus faecalis (Staphylococcus epidermidis), Staphylococcus aureus (Staphylococcus epidermidis) Staphylococcus hemolyticus (Staphylococcus haemolyticus), Staphylococcus hominis (Staphylococcus hominis), and Staphylococcus sacchari (Staphylococcus saccharolyticus).
10. The method of claim 7, wherein the infection comprises a bacterium selected from the group consisting of: pseudomonas aeruginosa (Pseudomonas aeruginosa), Pseudomonas fluorescens (Pseudomonas fluorescens), Stenotrophomonas maltophilia), Escherichia coli (Escherichia coli), Citrobacter freundii (Citrobacter freundii), Salmonella typhimurium (Salmonella typhimurium), Salmonella typhi (Salmonella typhi), Salmonella paratyphi (Salmonella paratyphi), Salmonella enteritidis (Salmonella enteritidis), Shigella dysenteriae (Shigella dysseniae), Shigella flexneri (Shigella flexneri), Shigella sonnei (Shigella flexneri), Shigella sonneri (Shigella sonneri), Shigella sonnei (Shigella sonnei), Salmonella sonnei (Shigella sonnei), Enterobacter cloacae (Enterobacter clausii), Enterobacter aerogenes (Enterobacter pneumoniae), Escherichia coli (Klebsiella pneumoniae), Yersinia enterocolibacillus (Yersinia enterocolitica), Escherichia coli (Yersinia Acinetobacter coli), Escherichia coli (Yersinia colibacillus acidogenic bacteria (Yersinia), Escherichia coli colibacillus acidogenic bacteria (Yersinia), Escherichia coli (Yersinia), Yersinia colibacillus coli (Yersinia), Enterobacter lactis), Escherichia coli (Yersinia), Escherichia coli colibacillus coli (Yersinia), Yersinia acidum acidicinolytica), Yersinia acidum (Yersinia), Yersinia acidici, Yersinia intermedia (Yersinia intermedia), Haemophilus influenzae (Haemophilus influenzae), Haemophilus parainfluenzae (Haemophilus parainfluenzae), Haemophilus haemolyticus (Haemophilus haemolyticus), Haemophilus parahaemolyticus (Haemophilus parahaemolyticus), Helicobacter pylori (Helicobacter pylori), Campylobacter foetus (Campylobacter focus), Campylobacter jejuni (Campylobacter jejuni), Campylobacter coli (Campylobacter coli), Vibrio cholerae (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), legionella pneumophila (Legionella pneumoniae), Listeria monocytogenes (Listeria monocytogenes), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Neisseria meningitidis (Neisseria meningitidis), Moraxella (Moraxella), Bacteroides fragilis (Bacteroides fragilis), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides ovatus (Bacteroides ovanus), Bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), Bacteroides monoides (Bacteroides uniflora), Bacteroides egeria exhi (Bacteroides degermoides gerthiii) and Bacteroides visceral sporangius (Bacteroides splanchnicus).
11. The method of claim 8, wherein the infection comprises the bacterium is pseudomonas aeruginosa.
12. The method of claim 8, wherein the infection comprises the bacterium is acinetobacter baumannii.
13. A method of treating a bacterial infection comprising administering to an individual in need thereof a compound having the structure:
Figure FDA0003510565680000041
or a pharmaceutically acceptable salt thereof,
and a further agent, wherein the further agent is ceftolozane or sulbactam.
14. A method of treating a bacterial infection comprising administering to an individual in need thereof a compound having the structure:
Figure FDA0003510565680000042
or a pharmaceutically acceptable salt thereof,
and a further agent, wherein the further agent is cefditorel.
15. The method of claim 13 or 14, wherein the pharmaceutically acceptable salt is an alkali metal or ammonium salt.
16. The method of claim 15, wherein the pharmaceutically acceptable salt is a sodium salt.
17. The method of any one of claims 14 to 16, wherein the sodium salt is
Figure FDA0003510565680000051
18. The method of any one of claims 14 to 16, wherein the sodium salt is
Figure FDA0003510565680000052
19. The method of any one of claims 14 to 16, wherein the sodium salt is
Figure FDA0003510565680000053
20. The method of any one of claims 14-19, wherein the compound and the additional agent are administered simultaneously.
21. The method of any one of claims 14 to 19, wherein the compound and the additional agent are administered sequentially.
22. The method of any one of claims 14 to 21, wherein the infection comprises the bacterium being pseudomonas aeruginosa.
23. The method of any one of claims 14 to 21, wherein the infection comprises the bacterium is acinetobacter baumannii.
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